Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma.

BACKGROUND: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. METHODS: Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. CONCLUSION: While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Talimogene laherparepvec resulting in near-complete response in a patient with treatment-refractory Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous tumour of neuroendocrine cell origin, which can grow rapidly and metastasise early. Localised disease is treated with surgery and radiotherapy. Disease that reaches a more advanced stage can be treated with a variety of different treatment modalities including surgery, radiotherapy, chemotherapy, radionuclide therapy, immunotherapy, and intralesional therapy. We report a case of a patient who had exhausted all local and systemic treatment options and who subsequently had an exceptional response to intralesional injection of Talimogene laherparepvec (TVEC).

Targeting Mutated KRAS Genes to Treat Solid Tumours.

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.

Contemporary management of locoregionally advanced melanoma in Australia and New Zealand and the role of adjuvant systemic therapy.

Australia and New Zealand have the highest incidence and mortality rates for melanoma in the world. Local surgery is still the standard treatment of primary cutaneous melanoma, and it is therefore important that surgeons understand the optimal care pathways for patients with melanoma. Accurate staging is critical to ensure a reliable assessment of prognosis and to guide treatment selection. Sentinel node biopsy (SNB) plays an important role in staging and the provision of reliable prognostic estimates for patients with cutaneous melanoma. Patients with stage III melanoma have a substantial risk of disease recurrence following surgery, leading to poor long-term outcomes. Systemic immunotherapies and targeted therapies, known to be effective for stage IV melanoma, have now also been shown to be effective as adjuvant post-surgical treatments for resected stage III melanoma. These patients should be made aware of this and preferably managed in an integrated multidisciplinary model of care, involving the surgeon, medical oncologists and radiation oncologists. This review considers the impact of a recent update to the American Joint Committee on Cancer (AJCC) staging system, the role of SNB for patients with high-risk primary melanoma and recent advances in adjuvant systemic therapies for high-risk patients.

Recent advancements in melanoma management.

The treatment options for patients with melanoma have expanded significantly over the past decade. In particular, the use of targeted therapy and immunotherapy has dramatically transformed the outlook for patients with advanced disease. These treatments are now being utilised as adjuvant therapy for patients with earlier stage melanoma after surgical resection. We review the latest updates for melanoma staging, surgical resection, radiotherapy and systemic therapies.

A retrospective analysis of eosinophilia as a predictive marker of response and toxicity to cancer immunotherapy.

AIM: To investigate eosinophilia as a potential on-treatment biomarker for patients receiving cancer immunotherapy. MATERIALS & METHODS: We evaluated the association between eosinophilia and treatment response and toxicity in a retrospective cohort of patients receiving cancer immunotherapy. RESULTS: The study involved 146 patients. Eosinophilia developed in 22%. Patients who developed eosinophilia were more likely to achieve disease control (p = 0.009), with every 0.1 × 109/l rise in eosinophil count, while receiving treatment was associated with a 28% relative increased chance achieving disease control. Although there was a trend toward improved survival, there was no significant association between eosinophilia and improved overall survival (p = 0.136). Patients with eosinophilia were more likely to develop toxicity (p = 0.042). CONCLUSION: Eosinophilia is a potentially useful biomarker warranting further prospective clinical investigation.

Duration of immunotherapy - should we continue ad infinitum?

The optimal duration of immunotherapy treatment for cancer patients is unknown. As the survival data from early immunotherapy trials mature we are beginning to appreciate how durable responses can be post-discontinuation. The purpose of this brief communication is to comment on treatment duration of immunotherapy in patients with melanoma and non-small cell lung cancer and to provide practice guidance in support of discontinuation.

Immunotherapy in Older Patients with Advanced Melanoma: A Review of the Current Evidence.

Despite the increasing incidence of metastatic melanoma in the older population, there is relatively limited specific data surrounding the use of immunotherapy for the treatment of advanced melanoma for patients above the age of 65 years. To date, there has not been a prospective trial done to evaluate the safety and efficacy of using immunotherapy to treat older patients with advanced melanoma. Older patients are often under-represented in clinical trials. In addition, older patients in clinical trials may have lower Eastern Cooperative Oncology Group (ECOG) performance score and fewer co-morbidities, and thus trial data may not truly reflect the experience of treating older patients. The purpose of this descriptive review is to examine the efficacy and safety data of the three currently approved immune checkpoint inhibitors for advanced melanoma treatment in older patients. Our review of available data established that the efficacy and tolerability of immunotherapy in older patients are comparable to results seen in younger patients. However, a dedicated, prospective, randomised trial to assess the safety, tolerability, and quality-of-life parameters of immunotherapy in the older population would provide further insight on the value of these treatments.

Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies.

BACKGROUND: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination. METHODS: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148). RESULTS: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. CONCLUSIONS: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.

Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists.

BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue; and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.

Carboplatin dosing in ovarian cancer: problems and pitfalls.

OBJECTIVE: Carboplatin is one of the most effective chemotherapeutic drugs for the treatment of ovarian cancer. It has simple pharmacokinetics and a predictable toxicity profile. The dose can be calculated effectively based on a patient's renal function as defined by the glomerular filtration rate (GFR). The measurement of the GFR is best done using radioisotopes, but this is expensive and not widely available, so many centers use equations to estimate GFR based on serum creatinine and other easily measured data. Recent changes in the measurement of serum creatinine, and a move toward isotope dilution mass spectrometry standardized values, have highlighted the difficulty in safely and effectively calculating doses of carboplatin in patients with ovarian cancer. METHODS: We have evaluated the currently available evidence for the most common methods of estimating and measuring GFR. We explored the problems and pitfalls with using each of these methods or equations and examined the effects of small changes in clinical parameters and the effect on carboplatin dose. RESULTS: Previous studies evaluating carboplatin's toxicity and efficacy used various different methods of GFR estimation and older methods of creatinine measurement. These may not translate to use with newer laboratory methods and may result in higher delivered doses than anticipated. CONCLUSIONS: The lack of consistency in carboplatin dosing, and changing creatinine values are a cause for concern if patient toxicity is a possible outcome. The need for new studies using new standard methods that can be widely used are urgently required to provide clarity in this area.